Heart failure is the pathophysiological state in which the heart is unable to pump blood at a sufficient rate through the circulation system of the body. This condition can result in congestive heart failure, a condition which arises when excess fluid accumulates due to the reduced pumping function of the heart. Myocardial infarction occurs when an interruption of the blood supply to the tissues of the heart causes necrosis of the region of tissue where blood supply has been deprived.
Ischemia is caused when an organ or part of the body fails to receive a sufficient blood supply. An organ that is deprived of an adequate blood supply is said to be hypoxic. Reperfusion occurs when blood flow recommences to an organ following temporary deprivation.
Reperfusion injury relates to damage which occurs to a tissue or an organ upon the return of the blood supply to a tissue following a period of ischemia. The absence of oxygen and nutrients during the period of ischemia results in a period of inflammation and oxidative damage when circulation returns. Examples of ischemia reperfusion injury include hypoxia, stroke, heart attack, chronic kidney failure or organ transplantation.
The etiology of reperfusion injury is multifactorial, although it is strongly associated with the pro-inflammatory immune response. Specifically, the return of blood flow to an area previously deprived of blood flow can result in the onset of a number of pro-inflammatory processes such as leukocyte adhesion and infiltration, free radical release and cytokine production. Furthermore, damage to the membranes of cells in areas which have undergone ischemia may result in the release of further free radicals. Programmed cell death (apoptosis) may also occur, while the migration of leukocytes to the area of ischemia may cause a blockage in capillaries, this resulting in a restriction of blood flow and an associated risk of further ischemia. Accordingly, restoration of blood flow following a period of ischemia can actually be more damaging than the ischemic event itself.
Therapeutic strategies for the treatment of myocardial infarction, whether pharmacological or mechanical, aim to open, or keep open, the occluded coronary artery in order to restore blood flow and perfusion of the myocardial tissue. Early restoration of blood flow in the infarct related artery and reperfusion of endangered viable myocardium improves clinical outcome. Paradoxically however, reperfusion itself results in necrosis and acceleration of apoptosis in cardiomyocytes, referred to as ischemia/reperfusion (I/R) injury. Since complications due to loss of viable myocardial tissue are still common after myocardial infarction, reperfusion alone seems insufficient to save endangered myocardium.
Reperfusion activates an inflammatory response mediated by the innate immune system. This activation of the innate immune system also leads to death of cardiomyocytes due to the release of pro-inflammatory cytokines and hazardous cell-to-cell interactions between neutrophils and cardiomyocytes. The intracellular Nuclear Factor-kappa B (NF-kB) signaling pathway mediates the transcription of pro-inflammatory genes in myocardial ischemia/reperfusion (I/R) injury. Further, the reintroduction of oxygen results in a greater production of damaging free radicals, an increase in pro-inflammatory mediators, and the associated onset of necrosis. The severity of reperfusion may vary due to a number of factors such as duration of ischemia, severity of ischemia and speed of reperfusion.
Toll-like Receptors (TLRs) form a family of pattern recognition receptors which have a key role in activating the innate immune response. Eleven Toll-like Receptors have been identified in humans to date. The members of the Toll-like Receptor family are highly conserved, with most mammalian species having between 10 to 15 Toll-like Receptors. Each Toll-like Receptor recognises specific pathogen-associated molecular signatures. Toll-like Receptor 2 (TLR2, CD282, TLR-2) can be activated by peptidoglycan, lipoproteins and lipoteichoic acid.
Studies to date have not fully elucidated the complex interplay of regulatory and inflammatory mechanisms which are triggered during ischemia and reperfusion. Furthermore, the nature and variability of ischemic reperfusion injury as expressed in different animal models, different patients and different tissues, has created further obstacles in relation to identifying methods for therapeutic intervention and prevention of ischemia reperfusion.
Following extensive experimentation, the present inventors have surprisingly identified that Toll-like Receptor 2 has an important role in the onset and progression of the innate inflammatory immune which is associated with ischemia reperfusion injury in a tissue or organ which has undergone a period of ischemia. The inventors have identified that compounds which have a binding specificity for Toll-like Receptor 2, and which function as Toll-like Receptor 2 agonists have utility in preventing aberrant pro-inflammatory immune responses which are associated with the development of reperfusion injury. The inventors have therefore identified that a therapeutic approach for the prevention and treatment of ischemia reperfusion injury, mediated by suppressing Toll-like Receptor 2 activation and signalling, would be potentially significant, particularly as the conserved nature of Toll-like Receptor 2 would suggest that such a therapeutic approach would provide a global approach to the treatment of this condition in a wide variety of species, tissues and cell types.